This proposed research is directed toward the design and development of general strategies for the syntheses of oxygenated natural products possessing biological activity. Of particular interest at the outset of these studies is the development of new methods for the stereoselective construction of Alpha-alkyl-Beta-hydroxy carbonyl compounds and functional arrays derived therefrom via the 1,3-dipolar cycloadditions of nitrile oxides to unactivated olefins and via the nucleophilic additions of 2-butenyl organometallic reagents to Beta-alkoxy aldehydes. The significant advantages that attend the use of substituted furans as intermediates in the stereoselective syntheses of hydropyranoid and other oxygenated natural products will also be exploited. Some potential entries to 3-acyl tetramic acids will also be explored. These methods will then be featured in the syntheses of: (1) tirandamycic acid and streptolic acid, the non-tetramic acid portions of tirandamycin and streptolydigin, which are important antibiotics that inhibit bacterial DNA-directed RNA polymerase, and streptolydigin also inhibits terminal deoxynucleotidyl transferase, an enzyme which is more abundant in tumor cells; (2) Prelog-Djerassi lactone, which is obtained by degradation of the antibiotics methymycin or narbomycin and possesses architectural features common to a range of macrolide antibiotics; (3) pseudomonic acids A and C, which are antibiotics that function as competitive inhibitors of isoleucyl-tRNA synthetase and are effective antimicrobial agents; (4) erythronolide A and B, which are the aglycones of the medicinally important macrolide antibiotics erythromycin A and B, respectively; and (5) phyllanthocin, the aglycone of the potent antileukemic glycoside phyllanthoside. The availability of tirandamycic acid and streptolic acid together with methods for coupling them with various tetramic acids will allow the syntheses of tirandamycin, streptolydigin and derivatives thereof for biological evaluation as anti-cancer agents. Similarly, with phyllanthocin in hand it shall be possible to prepare phyllanthoside and other related glycosides for screening for anticancer activity. Selected synthetic intermediates and derivatives of the natural products will be submitted to The Upjohn Company, McNeil Laboratories, and/or the National Cancer Institute for biological screening.